This application constitutes the fifth competitive renewal of The Mount Sinai School of Medicine Alzheimer's Disease Research Center. We have used the strengths of our well established center to address the new vision of the NIA Center program. We have proposed standardized assessment to be used at all our sites and the EITC core will assist us with developing procedures manual, training materials and certification methods to insure that the evaluations can be reliably collected from a range of research staff. The newly established Data Management Core has been intimately involved in the development of the data collection instruments to insure that they can be readily entered into the data warehouse, that clinical and neuropathological information can be accessed and integrated and that the extraction of the NACC data set can be accomplished seamlessly. This submission highlights our long standing accomplishments in clinical evaluation and neuropathological characterization of healthy elderly, mild cognitive impairment and early AD. In project 0023, we will integrate clinical and neuropathological to trace the earliest indicators of cognitive change in aging and dementia. In Projects 0024 and 0028, leading notions of potential etiologic mechanisms are explored in depth. In this renewal the following cores and projects are proposed: 1. Administrative Core A (M. Sano/J. Morrison) 2. Clinical Research Support Core/ Elmhurst Satellite (M. Sano) 3. Data Management Core C (V, Haroutunian) 4. Neuropathology Core D (D.Perl/V.Haroutunian) 5. Education and Information Transfer Core E (M.Sewell/M.Sano) 6. Project #0023: Selective Neuronal Pathology in the Development of Dementia (P. Hof) 7. Project #0024: Identification and characterization of first messengers that regulate APP processing (J. Buxbaum) 8. Project #0028: PS1 Regulates Cleavage and Function of EphrinB ligand and EphB Receptor (A.Georgakopoulos)